tbuckley/cabot-search huggingface dataset:
Abstract 135: Age-related immunosenescence and cancer drug toxicity and efficacy in C57BL/6J syngeneic model
Authors: Jiwon Yang, Andrew Schile, Mingshan Cheng, James G. Keck
Journal: Cancer Research (2022)

Abstract Cancer has a higher incidence in the elderly and immunotherapy is widely applied to this population. However, the majority of preclinical studies assessing drug toxicity and efficacy have been done in young healthy mice. Immunosenescence is a state of aging-related gradual deterioration of the immune system in the elderly. Here, we established tumor models in aged mice that show immunosenescence for a better representation of cancer patients, and to examine the effects of aging and immunosenescence on cancer drug efficacy and toxicity. Young (7 weeks), mid-aged (54-58 weeks), and aged (76-78 weeks) C57BL/6J female mice were used for this study. Syngeneic tumor models were established using three different mouse cancer cell lines, B16-F10 melanoma, MC38 colon adenocarcinoma, and E0771 breast cancer. Age-related tumor growth kinetics varied based on tumor models. Specifically, aging did not affect tumor growth kinetics of B16-F10 tumors, while aged mice showed slowed growth of MC38 tumors and faster growth of E0771 tumors. To evaluate the maximum tolerated dose, young and aged mice were dosed with the standard of care cancer drugs (docetaxel, cisplatin, and doxorubicin) and body weight was monitored three times a week. Aged mice showed higher toxicity against standard care cancer drugs compared to young counterparts. Next, we performed efficacy study using checkpoint inhibitor. Young, mid-aged, and aged mice bearing MC-38 tumor were treated with isotype control or Anti-PD1 (8 mg/kg), intravenously, twice weekly for 3 weeks. Whole blood and tumor samples were collected for immune cell profiling. Comparisons of PD-1 response in the various age groups showed that anti-PD1 treatment showed significant suppression of tumor growth in all age groups with the MC38 tumors, with the greatest effect in aged mice. We also found that anti-PD1 treatment increased T cell infiltration into the tumor, and that regulatory T cells in the tumor are decreased in aged mice. In conclusion, we established syngeneic tumor models using aged mice, and found aged mice exhibit higher toxicity against drugs. The effect of aging on tumor growth kinetics varies depending on the models. Differences in immune cell infiltration in the tumor might be an underlying event that causes age-related differences in response to anti-PD1 treatment. The integration of aging in cancer research could potentially bridge the gap between preclinical studies and clinical outcomes. Citation Format: Jiwon Yang, Andrew Schile, Mingshan Cheng, James G. Keck. Age-related immunosenescence and cancer drug toxicity and efficacy in C57BL/6J syngeneic model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 135.
Abstract 5850: p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis
Authors: Titilope M. Dokunmu, Sandra C. Opara, Omiete U. Awani
Journal: Cancer Research (2022)

Abstract Background: With increasing incidence of cancers globally and limited resources in some affected countries, repurposing existing drugs for reducing tumorigenesis is highly important. Artemisinin and caffeine have potent anti-oxidative and anti-cancer properties, although they are therapies for other diseases. When p53 is activated, it repairs DNA damage, prevents tumorigenesis and induces apoptosis whereas nitric oxide is a pro-apoptotic modulator which can upregulate p53 thereby reducing tumorigenesis. We evaluated the biochemical and p53 gene modulatory effects of doses of artemisinin-caffeine combination on breast, lung and liver tumors in rats induced with DMBA. Methods: After due ethical approval, 30 animals were treated with 40mg/kg single dose of 7,12-dimethylbenzene anthracene (DMBA) as a model for DNA damage and induction of carcinogenesis. Five animals each received low dose artemisinin (4mg/kg), low dose caffeine (25mg/kg), low dose combination of Art + Caff (4+25mg/kg), high dose combination of Art + Caff (8+50 mg/kg) or no treatment. All treatment doses were orally administered daily for two weeks post-DMBA treatment, normal control received saline. Nitric oxide levels were assessed and p53 relative gene expression was determined by primer-specific RT-PCR (GAPDH was used as loading control) and amplicons were resolved by gel electrophoresis. Results: DMBA induced lesions in breast, liver, and lung tissues were evident from histology analysis, compared to untreated group. In all 3 tissues, low dose caffeine and combination of Art + Caff significantly reduced p53 gene expression (p &amp;lt; 0.05), but there was significant increase in of p53 expression in low dose Art and high dose Art + Caff groups, which were similar to DMBA group (p&amp;lt;0.05). There was also decrease in nitric oxide levels in treated groups compared to DMBA group. Conclusions: This study shows a dose-dependent anticancer effects of caffeine and artemisinin combination on p53 gene and nitric oxide regulation and hence can mitigate against tumorigenesis. Citation Format: Titilope M. Dokunmu, Sandra C. Opara, Omiete U. Awani. p53 gene expression and nitric oxide levels after artemisinin-caffeine treatment in breast, lungs and liver of DMBA-induced tumorigenesis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5850.
Abstract 124: PRDX4 links ER-specific redox vulnerability to innate immunity in pancreatic cancer
Authors: Lucie Malbeteau, Pallavi Jain, Shane Harding, Bradley Wouters, Marianne Koritzinsky
Journal: Cancer Research (2022)

Abstract The prognosis of pancreatic ductal carcinoma (PDAC) remains dismal, with an overall 5-year survival rate of 7%. Immunotherapy (IT) has provided new hope for other hard-to-treat cancers, but PDAC has shown striking resistance to IT by orchestrating mechanisms of immune escape. This spurs an interest to identify novel strategies to improve PDAC sensitivity to IT. We recently unveiled that perturbating redox homeostasis by targeting the antioxidant protein peroxiredoxin 4 (PRDX4) render pancreatic cancer cells highly vulnerable. PRDX4 supports redox homeostasis by metabolizing H2O2 in the endoplasmic reticulum (ER), and its loss leads to oxidative stress and toxicity. Interestingly, cell death induced by PRDX4 depletion is accompanied by DNA damage and accumulation of cytosolic DNA, a potent primer for immune therapy. In line with that, PRDX4 knockdown results in the transcriptional upregulation of inflammatory genes, including type I interferons (IFNs), primary cytokines and interferon-stimulated genes (ISGs). Importantly, our data indicate that this induction is dependent on the critical regulator of the innate immune responses, STING, as treatment with a STING inhibitor, or a STING knockdown, substantially blunts their upregulation. It is known that following DNA damage detection, the ER-localized STING translocates to the Golgi, where it associates with the kinase TBK1 and mediates the induction of inflammatory target genes, depending on IRF3 and NF-κB transcription factors. We observe an activation of downstream STING effectors upon PRDX4 loss, and co-depletion with NFκB significantly rescues the upregulation of those genes. As such, we propose that PRDX4 links ER-specific redox vulnerability to innate immunity signaling in PDAC. Since PRDX4 loss causes increased DNA damage and inflammatory signaling, our preliminary data suggest that PRDX4 could be a novel therapeutic target that may act synergistically with immune checkpoint inhibitors. Citation Format: Lucie Malbeteau, Pallavi Jain, Shane Harding, Bradley Wouters, Marianne Koritzinsky. PRDX4 links ER-specific redox vulnerability to innate immunity in pancreatic cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 124.
Abstract 5724: Loss of SWI/SNF chromatin remodeling alters NRF2 signaling in human cancers
Authors: Vinh Nguyen, Travis Shranck, Samera Hamad, Bernard Weissman
Journal: Cancer Research (2022)

Abstract Next-generation sequencing studies of lung cancer has shown a significant number of mutations in two previously unrecognized regulatory pathways. Activating mutations, the NF-E2-related factor 2 (NFE2L2, NRF2) transcription factor induces constitutive expression of cytoprotective and redox maintenance genes. Inactivating mutations in members of the SWI/SNF chromatin-remodeling complex, especially SMARCA4 (BRG1) and ARID1A, lead to changes in nucleosome positioning and gene expression. Here, we show that loss of SWI/SNF complex function activated a subset of NRF2-mediated transcriptional targets. Using a series of isogenic NSCLC lines with reduced or depleted BRG1 and/or BRM expression, we observed significantly increased expression and protein levels of the NRF2-target genes HMOX1 and GSTM4. RNA sequencing of BRG1-proficient and -deficient cell lines confirmed changes in KEAP1-NRF2 target gene expression as well as identified novel targets of the SWI/SNF complex. Importantly, low BRG1 expression levels in primary human NSCLC tumors correlated with increased NRF2-target gene expression. In addition to BRG1 levels, we examined loss of ARID1A across primary human tumors and found ARID1A deficiency was associated with altered NRF2 signaling. The tumors with the highest frequency of altered NRF2 signaling were lung squamous (LUSC) and head and neck squamous (HNSCC), cancers strongly associated with environmental toxicants. Interestingly ARID1A loss depressed NRF2 signaling in LUSC while amplifying it in HNSCC, an observation we are exploring mechanistically in cell line knock out models. Our data demonstrate that loss of SWI/SNF in lung cancer results in activation of the NRF2/KEAP1 pathway and increased expression of a subset of its downstream targets. These data provide an additional molecular explanation for why patients harboring SWI/SNF mutations show a poor prognosis. Our results also potentially link mutations in SWI/SNF complex components, that occur in &amp;gt;20% of human cancers, with exposure to environmental toxicants. A better understanding of these mechanism may yield novel insights into the design of targeted treatment modalities for human lung cancers. Citation Format: Vinh Nguyen, Travis Shranck, Samera Hamad, Bernard Weissman. Loss of SWI/SNF chromatin remodeling alters NRF2 signaling in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5724.
Abstract 1701: Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment
Authors: Vincent Liu, Katalin Sandor, Bence Daniel, Lionel Berthoin, Shan Sabri, Sofia Panagiotopoulou, Yajie Yin, Kamir Hiam-Galvez, Rene Sit, Zi Fan, Brendan Galvin, Omar Khan, Natalie Bezman, Jane Grogan, Brooke Howitt, Grace Zheng, Caleb Lareau, Ansuman Satpathy
Journal: Cancer Research (2022)

Abstract Tumor initiation and progression are the result of a close interplay between malignant cells and immune cells. While single-cell genomics has enabled the molecular dissection of the cellular heterogeneity underlying complex cancers, many facets of tumor microenvironments remain unresolved. In particular, the ontogeny of myeloid cells have not been fully understood in human tumors, although the source and expansion of macrophages have been suggested to underlie tumor development and metastasis in mice. In an effort to comprehensively characterize these tumor microenvironments, we profiled endometrial, ovarian, and metastatic tumors from 16 patients using CITE-seq (an atlas of 258,810 cells) and mitochondrial single-cell ATAC-seq (mtscATAC-seq; consisting of 173,820 cells). Our multi-omic analyses reveal the heterogeneity of tumor-infiltrating immune cells at clonal, epigenetic, transcriptomic, and proteomic levels. Notably, all tumor types harbored diverse exhausted T cell subsets, including terminal and precursor exhausted T cells, and gamma/delta T cells. Clonal somatic variant analysis between tumor tissues and peripheral blood mononuclear cells identified blood-derived monocytes, rather than embryonically derived cells, as the origin of macrophages within gynecological tumors. Further, our analyses show that macrophages expand minimally within the tumor microenvironment, suggesting that they may be continuously replenished by blood, an observation that may facilitate new approaches for cancer immunotherapy. In total, our dataset represents the first multi-modal single cell atlas of gynecologic tumors and reveals distinct features of T cell heterogeneity and myeloid expansions in complex tumor microenvironments. Citation Format: Vincent Liu, Katalin Sandor, Bence Daniel, Lionel Berthoin, Shan Sabri, Sofia Panagiotopoulou, Yajie Yin, Kamir Hiam-Galvez, Rene Sit, Zi Fan, Brendan Galvin, Omar Khan, Natalie Bezman, Jane Grogan, Brooke Howitt, Grace Zheng, Caleb Lareau, Ansuman Satpathy. Single-cell multi-omic profiling and clonal tracing of the human gynecological tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1701.
Cost-effectiveness of polatuzumab vedotin combined with chemoimmunotherapy in untreated diffuse large B-cell lymphoma
Authors: Swetha Kambhampati, Monica Saumoy, Yecheskel Schneider, Stacy Pak, Lihua Elizabeth Budde, Matthew G. Mei, Tanya Siddiqi, Leslie L. Popplewell, Yi-Ping Wen, Jasmine Zain, Stephen J. Forman, Larry W. Kwak, Steven T. Rosen, Alexey V. Danilov, Alex F. Herrera, Nikhil R. Thiruvengadam
Journal: Blood (2022)

In patients with treatment-naive diffuse large B-cell lymphoma (DLBCL), the POLARIX study (A Study Comparing the Efficacy and Safety of Polatuzumab Vedotin With Rituximab-Cyclophosphamide, Doxorubicin, and Prednisone [R-CHP] Versus Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone [R-CHOP] in Participants With Diffuse Large B-Cell Lymphoma) reported a 6.5% improvement in the 2-year progression-free survival (PFS), with no difference in overall survival (OS) or safety using polatuzumab vedotin, rituximab, cyclophosphamide, doxorubicin, and prednisone (pola-R-CHP) compared with standard rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). We evaluated the cost-effectiveness of pola-R-CHP for DLBCL. We modeled a hypothetical cohort of US adults (mean age, 65 years) with treatment-naive DLBCL by developing a Markov model (lifetime horizon) to model the cost-effectiveness of pola-R-CHP and R-CHOP using a range of plausible long-term outcomes. Progression rates and OS were estimated from POLARIX. Outcome measures were reported in incremental cost-effectiveness ratios, with a willingness-to-pay (WTP) threshold of $150 000 per quality-adjusted life-year (QALY). Assuming a 5-year PFS of 69.6% with pola-R-CHP and 62.7% with R-CHOP, pola-R-CHP was cost-effective at a WTP of $150 000 (incremental cost-effectiveness ratio, $84 308/QALY). pola-R-CHP was no longer cost-effective if its 5-year PFS was 66.1% or lower. One-way sensitivity analysis revealed that pola-R-CHP is cost-effective up to a cost of $276 312 at a WTP of $150 000. pola-R-CHP was the cost-effective strategy in 56.6% of the 10 000 Monte Carlo iterations at a WTP of $150 000. If the absolute benefit in PFS is maintained over time, pola-R-CHP is cost-effective compared with R-CHOP at a WTP of $150 000/QALY. However, its cost-effectiveness is highly dependent on its long-term outcomes and costs of chimeric antigen receptor T-cell therapy. Routine usage of pola-R-CHP would add significantly to health care expenditures. Price reductions or identification of subgroups that have maximal benefit would improve cost-effectiveness.
Abstract 5506: CD30 co-stimulatory domain enhances the efficacy of chimeric antigen receptor-engineered γδT cells
Authors: Hyun-Il Cho, Chung-Hyo Kang, Sang-Eun Lee, In-Sil Song, Jung-Min Ha, Seon-Duk Lee, Hyun-Jung Sohn, Tai-Gyu Kim
Journal: Cancer Research (2022)

Abstract Adoptive transfer of immune killer cells genetically engineered to express chimeric antigen receptors (CARs) has demonstrated a feasible and effective approach against numerous types of cancers. Among the killer cells, γδT cells possessing a wide range of antigen-independent tumor recognition and low risk of developing GVHD offer a chance to develop CAR-engineered allogenic ‘off-the-shelf’ cellular therapeutics. Successful tumor eradication primarily depends on providing optimized signals affecting the proliferation, persistence, antitumor activity and cytokine secretion of CAR-γδT cells. We describe here a novel CD30 costimulatory domain for CAR signaling, which is known to be involved in cell anti-apoptosis, activation and proliferation. Conventional αβT cells and innate γδT cells activated by a CD30-ζ signaling-CAR displayed similar levels of cytolytic efficacies and cytokine secretion against antigen-expressing cancer cell lines as those of other CAR containing commonly used costimulatory domains CD28, CD27, 4-1BB, OX40, and ICOS. Furthermore, the third-generation CARs including the CD30 costimulatory domain retained potent antitumor efficacies independent of their position or type of partner costimulatory domain. More significantly, CAR-γδT cells containing CD30-ζ signaling revealed effective cytolytic activities against several solid cancer cell lines based on its antigen-recognizing antibody fragments. Our findings suggest that the CD30 costimulatory domain could be an attractive candidate for developing CAR-engineered killer cell therapeutics and may be applicable for the design of numerous antigen-recognizing CAR constructs, with an emphasis on targeting solid tumors. Citation Format: Hyun-Il Cho, Chung-Hyo Kang, Sang-Eun Lee, In-Sil Song, Jung-Min Ha, Seon-Duk Lee, Hyun-Jung Sohn, Tai-Gyu Kim. CD30 co-stimulatory domain enhances the efficacy of chimeric antigen receptor-engineered γδT cells [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5506.
Abstract 5062: Identification of synthetic lethal gene interactions to discover novel cancer vulnerabilities and guide drug development
Authors: Mukti Parikh, Manuel García-Quismondo, Neel S. Madhukar, Coryandar Gilvary
Journal: Cancer Research (2022)

Abstract Poor treatment responses in patients and drug resistance are main challenges in the clinic which can arise due an incomplete understanding of genetic dependencies within cancers and an ill defined patient population. Identifying synthetic lethal (SL) relationships between a gene pair, where loss of either of the participating genes has no effect on cancer cells, however simultaneous disruption of both genes leads to cancer cell death, can uncover major survival mechanisms and expose vulnerabilities within cancers. In spite of advances in CRISPR or RNAi based loss of function screening it is difficult to identify these gene interactions solely by experimentation due to the vast mutational landscape of cancers, inability of cell lines to capture clinically relevant mutations, and large number of possible SL gene combinations. Furthermore, large scale CRISPR/RNAi screens are prone to false positive results, leading to erroneous identification of gene interactions. We developed a machine learning model to identify SL genetic interactions by integrating pathway, ontology, genomic, and loss of function features on all gene pairs. This included features, which have been shown to be predictive of SL pairs such as, involvement in important cancer hallmark processes or signaling pathways, co-expression profile in patient cancers, and many more. The model was trained using SL pairs from published large scale experimental screens across several cancer types, ultimately enabling the prediction of cancer agnostic SL pairs. Non-SL pairs had to be computationally defined using post-perturbation gene expression profiles due to the lack of published data annotating non-SL pairs. The model showed significant predictive performance (AUROC = 0.94, AUPRC = 0.93, Specificity = 0.91), additionally, when tested on a gold standard, biologically verified set of SL gene pairs across several cancer types, the model showed good generalizability. We leveraged the model to identify key clinically relevant SL relationships and uncover complementary mechanisms tied to pro-survival processes. By identifying SL gene interacting pairs, our platform can help gain a better understanding of dominant mechanisms driving cancers and guide the discovery of novel therapies, biomarkers, and combination therapies early on during drug development. Citation Format: Mukti Parikh, Manuel García-Quismondo, Neel S. Madhukar, Coryandar Gilvary. Identification of synthetic lethal gene interactions to discover novel cancer vulnerabilities and guide drug development [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 5062.